Bacterial infections are still a major cause of morbidity and mortality, and biodefense category A and B pathogens include at least 18 bacteria that are potential threats to public health in case of their use in biological warfare or bioterrorism attack. The exposure from such an attack may not involve natural ways of transmission of these bacteria, but rather would likely involve contaminated air, objects, food, or water supply. Furthermore, the biological warfare or bioterrorism agent that will be used may not be initially known or may be a mixture of several agents. Therefore, an immediate and broad-based protection, effective against many bacteria, would be most beneficial in early stages of host defense against such an attack, to prevent or stop the infection at the portal of entry (which is likely to be skin, eyes, gastrointestinal tract, and upper respiratory tract). Because of broad specificity of innate immunity mechanisms for many bacteria (through their pattern recognition receptors), innate immunity is likely to be the most effective first line of defense to combat such bacterial infections immediately after the initial exposure. Thus, enhancing host antibacterial innate immunity at the site of contact with bacteria, including category A and B pathogens, could prevent establishment of infection or complement other therapies, and thus save lives in a biological warfare or a bioterrorism attack. Therefore, the goal of this project is to determine if human peptidoglycan recognition proteins (PGRPs), a newly discovered family of antibacterial pattern recognition molecules, can be applied to enhance host defenses against bacterial infections (including biodefense category A and B bacterial pathogens). Such an application will first require understanding of the mechanism of their antibacterial effect. This project will: first, determine the extent of antibacterial activity of PGRPs against a variety of bacteria (including category A and B bacterial pathogens); second, look for alternative splice forms of PGRPs with higher antibacterial activity; third, determine the mechanism of antibacterial effect of PGRPs and optimize the in vitro conditions for the antibacterial effect of PGRPs; and fourth, determine if PGRPs have protective or therapeutic effects in mouse infection models, when applied to the initial site of contact with selected category A and B bacterial pathogens.